The present study aims to establish a relationship between serum AMH levels and age in a large group of women living in Bulgaria, as well as to establish reference age-specific AMH levels in women that would serve as an initial estimate of ovarian age. A total of 28,016 women on the territory of the Republic of Bulgaria were tested for serum AMH levels with a median age of 37.0 years (interquartile range 32.0 to 41.0). For women aged 20 - 29 years, the Bulgarian population has relatively high median levels of AMH, similar to women of Asian origin. For women aged 30 - 34 years, our results are comparable to those of women living in Western Europe. For women aged 35 - 39 years, our results are comparable to those of women living in the territory of India and Kenya. For women aged 40 - 44 years, our results were lower than those for women from the Western European and Chinese populations, close to the Indian and higher than Korean and Kenya populations, respectively. Our results for women of Bulgarian origin are also comparable to US Latina women at age 30, 35 and 40 ages. On the base on constructed a statistical model to predicting the decline in AMH levels at different ages, we found non-linear structure of AMH decline for the low AMH < 1 group, while for the other two AMH groups (1 ≤ AMH ≤ 3.5 and AMH > 3.5) the dependence of the decline of AMH on age was confirmed as linear. In conclusion, we evaluated the serum level of AMH in Bulgarian women and established age-specific AMH percentile reference values based on a large representative sample. We have developed a prognostic statistical model that can facilitate the application of AMH in clinical practice and the prediction of reproductive capacity and population health.
References
[1]
Gunasheela, D., Murali, R., Appaneravanda, L., et al. (2021)Age-Specific Distribution of Serum Anti-Mullerian Hormone and Antral Follicle Count in Indian Infertile Women. Journal of Human Reproductive Sciences, 14, 372-379. https://doi.org/10.4103/jhrs.jhrs_65_21
[2]
Scheffer, J.A.B., Scheffer, B., Scheffer, R., Florencio, F., Grynberg, M. and Lozano, D.M. (2018) Are Age and Anti-Müllerian Hormone Good Predictors of Ovarian Reserve and Response in Women Undergoing IVF? JBRA Assisted Reproduction, 22, 215-220. https://doi.org/10.5935/1518-0557.20180043
[3]
Gleicher, N., Weghofer, A. and Barad, D.H. (2011) Defining Ovarian Reserve to Better Understand Ovarian Aging. Reproductive Biology and Endocrinology, 9, Article No. 23. https://doi.org/10.1186/1477-7827-9-23
[4]
Sills, E.S., Alper, M.M. and Walsh, A.P. (2009) Ovarian Reserve Screening in Infertility: Practical Applications and Theoretical Directions for Research. European Journal of Obstetrics & Gynecology and Reproductive Biology, 146, 30-36. https://doi.org/10.1016/j.ejogrb.2009.05.008
[5]
Al-Azemi, M., Killick, S.R., Duffy, S., Pye, C., Refaat, B., Hill, N., et al. (2011)Multimarker Assessment of Ovarian Reserve Predicts Oocyte Yield after Ovulation Induction. Human Reproduction, 26, 414-422. https://doi.org/10.1093/humrep/deq339
[6]
Visser, J.A., de Jong, F.H., Laven, J.S.E. and Themmen, A.P.N. (2006) Anti-Müllerian Hormone: A New Marker for Ovarian Function. Reproduction, 131, 1-9. https://doi.org/10.1530/rep.1.00529
[7]
Barad, D.H., Weghofer, A. and Gleicher, N. (2011) Utility of Age-Specific Serum Anti-Müllerian Hormone Concentrations. Reproductive BioMedicine Online, 22, 284-291. https://doi.org/10.1016/j.rbmo.2010.12.002
[8]
La Marca, A., Sighinolfi, G., Giulini, S., Traglia, M., Argento, C., Sala, C., et al. (2010)Normal Serum Concentrations of Anti-Müllerian Hormone in Women with Regular Menstrual Cycles. Reproductive BioMedicine Online, 21, 463-469. https://doi.org/10.1016/j.rbmo.2010.05.009
[9]
Overbeek, A., Broekmans, F.J., Hehenkamp, W.J., et al. (2012)Intra-Cycle Fluctuations of Anti-Müllerian Hormone in Normal Women with a Regular Cycle: A Re-Analysis. Reproductive BioMedicine Online, 24, 664-669. https://doi.org/10.1016/j.rbmo.2012.02.023
[10]
La Marca, A., Spada, E., Grisendi, V., et al. (2012)Normal Serum Anti-Müllerian Hormone Levels in the General Female Population and the Relationship with Reproductive History. European Journal of Obstetrics & Gynecology and Reproductive Biology, 163, 180-184. https://doi.org/10.1016/j.ejogrb.2012.04.013
[11]
Nelson, S.M., Ewing, B.J., Gromski, P.S. and Briggs, S.F. (2023) Contraceptive-Specific Antimullerian Hormone Values in Reproductive-Age Women: A Population Study of 42,684 Women. Fertility and Sterility, 119, 1069-1077. https://doi.org/10.1016/j.fertnstert.2023.02.019
[12]
Kevenaar, M.E., Meerasahib, M.F., Kramer, P., et al. (2006)Serum Anti-Mullerian Hormone Levels Reflect the Size of the Primordial Follicle Pool in Mice. Endocrinology, 147, 3228-3234. https://doi.org/10.1210/en.2005-1588
[13]
La Marca, A., Sighinolfi, G., Radi, D., et al. (2010)Anti-Müullerian Hormone (AMH) as a Predictive Marker in Assisted Reproductive Technology (ART). Human Reproduction Update, 16, 113-130. https://doi.org/10.1093/humupd/dmp036
[14]
Nelson, S.M., Yates, R.W., Lyall, H., Jamieson, M., Traynor, I., Gaudoin, M., et al. (2009)Anti-Mullerian Hormone-Based Approach to Controlled Ovarian Stimulation for Assisted Conception. Human Reproduction, 24, 867-875. https://doi.org/10.1093/humrep/den480
[15]
La Marca, A., Papaleo, E., Grisendi, V., Argento, C., Giulini, S. and Volpe, A. (2012) Development of a Nomogram Based on Markers of Ovarian Reserve for the Individualisation of the Follicle-Stimulating Hormone Starting Dose in vitro Fertilisation Cycles. BJOG: An International Journal of Obstetrics & Gynaecology, 119, 1171-1179. https://doi.org/10.1111/j.1471-0528.2012.03412.x
[16]
Muttukrishna, S., McGarrigle, H., Wakim, R., Khadum, I., Ranieri, D.M. and Serhal, P. (2005) Antral Follicle Count, Anti-Mullerian Hormone and Inhibin B: Predictors of Ovarian Response in Assisted Reproductive Technology? BJOG: An International Journal of Obstetrics & Gynaecology, 112, 1384-1390. https://doi.org/10.1111/j.1471-0528.2005.00670.x
[17]
Gnoth, C., Schuring, A.N., Friol, K., Tigges, J., Mallmann, P. and Godehardt, E. (2008) Relevance of Anti-Mullerian Hormone Measurement in a Routine IVF Program. Human Reproduction, 23, 1359-1365. https://doi.org/10.1093/humrep/den108
[18]
Penarrubia, J., Fabregues, F., Manau, D., Creus, M., Casals, G., Casamitjana, R., et al. (2005)Basal and Stimulation Day 5 Anti-Mullerian Hormone Serum Concentrations as Predictors of Ovarian Response and Pregnancy in Assisted Reproductive Technology Cycles Stimulated with Gonadotropinreleasing Hormone Agonist-Gonadotropin Treatment. Human Reproduction, 20, 915-922. https://doi.org/10.1093/humrep/deh718
[19]
Tehrani, F.R., Solaymani-Dodaran, M., Tohidi, M., Gohari, M.R. and Azizi, F. (2013) Modeling Age at Menopause Using Serum Concentration of Anti-Mullerian Hormone. The Journal of Clinical Endocrinology & Metabolism, 98, 729-735. https://doi.org/10.1210/jc.2012-3176
[20]
Broer, S.L., Eijkemans, C., Scheffer, G.J., van Rooij, I.A., de,Vet, A., Themmen, A.P., et al. (2011)Anti-Mullerian Hormone Predicts Menopause: A Long-Term Follow-Up Study in Normoovulatory Women. The Journal of Clinical Endocrinology & Metabolism, 96, 2532-2539. https://doi.org/10.1210/jc.2010-2776
[21]
Fong, S.L., Visser, J.A., Welt, C.K., de Rijke, Y.B., Eijkemans, M.J., Broekmans, F.J., et al. (2012)Serum Anti-Mullerian Hormone Levels in Healthy Females: A Nomogram Ranging from Infancy to Adulthood. The Journal of Clinical Endocrinology and Metabolism, 97, 4650-4655. https://doi.org/10.1210/jc.2012-1440
[22]
Almog, B., Shehata, F., Suissa, S., Holzer, H., Shalom-Paz, E., La Marca, A., et al. (2011)Age-Related Normograms of Serum Antimullerian Hormone Levels in a Population of Infertile Women: A Multicenter Study. Fertility and Sterility, 95, 2359-363. https://doi.org/10.1016/j.fertnstert.2011.02.057
[23]
Тal, R., Seifer, D.B., Khanimov, M., Schwartz, E., Grazi, R.V. and Malter, H.E. (2012) Antimullerian Hormone (AMH) Is an Independent Predictor of Twin versus Singleton Pregnancy in Fresh ART Cycles. Reproductive BioMedicine Online, 26, 360-367. https://doi.org/10.1016/j.rbmo.2012.12.002
[24]
Yates, A.P., Rustamov, O., Roberts, S.A., Lim, H.Y., Pemberton, P.W., Smith, A., et al. (2011)Anti-Mullerian Hormone-Tailored Stimulation Protocols Improve Outcomes Whilst Reducing Adverse Effects and Costs of IVF. Human Reproduction, 26, 2353-2362. https://doi.org/10.1093/humrep/der182
[25]
Seifer, D.B., Golub, E.T., Lambert-Messerlian, G., et al. (2009)Variations in Serum Müllerian Inhibiting Substance between White, Black, and Hispanic Women. Fertility and Sterility, 92, 1674-1678. https://doi.org/10.1016/j.fertnstert.2008.08.110
[26]
Schuh-Huerta, S.M., Johnson, N.A., Rosen, M.P., Sternfeld, B., Cedars, M.I. and Reijo Pera, R.A. (2012) Genetic Variants and Environmental Factors Associated with Hormonal Markers of Ovarian Reserve in Caucasian and African American Women. Human Reproduction, 27, 594-608. https://doi.org/10.1093/humrep/der391
[27]
Republic of Bulgaria. National Statistical Institute. https://www.nsi.bg/en/search/node?keys=Ethnocultural characteristics of the population
[28]
Fauser, B.C.J.M., Adamson, G.D., Boivin, J., Chambers, G.M., de Geyter, C., Dyer, S., et al. (2024) Declining Global Fertility Rates and the Implications for Family Planning and Family Building: An IFFS Consensus Document Based on a Narrative Review of the Literature. Human Reproduction Update.
[29]
Gassner, D. and Jung, R. (2014) First Fully Automated Immunoassay for Anti-Müllerian Hormone. Clinical Chemistry and Laboratory Medicine, 52, 1143-1152. https://doi.org/10.1515/cclm-2014-0022
[30]
Hyldgaard, J., Bor, P., Ingerslev, H.J. and Tørring, N. (2015) Comparison of Two Different Methods for Measuring Anti-Mullerian Hormone in a Clinical Series. Reproductive Biology and Endocrinology, 13, Article No. 107. https://doi.org/10.1186/s12958-015-0101-5
[31]
Nelson, S.M., Pastuszek, E., Kloss, G., et al. (2015)Two New Automated, Compared with Two Enzyme-Linked Immunosorbent, Antimullerian Hormone Assays. Fertility and Sterility, 104, 1016-1021.E6. https://doi.org/10.1016/j.fertnstert.2015.06.024
[32]
Choi, R., Park, W., Chun, G., Lee, S.G. and Lee, E.H. (2023) Investigation of the Prevalence of Diminished Ovarian Reserve in Korean Women of Reproductive Age. Journal of Clinical Medicine, 12, Article 5099. https://doi.org/10.3390/jcm12155099
[33]
Hao, Y., Yang, R., Li, J., Zhou, Z., Qian, W., Zhang, J., et al. (2022) Age-Specific Random Day Serum Antimüllerian Hormone Reference Values for Women of Reproductive Age in the General Population: A Large Chinese Nationwide Population-Based Survey. American Journal of Obstetrics & Gynecology, 227, 883.E1-883.E18. https://doi.org/10.1016/j.ajog.2022.07.029
[34]
Nelson, S.M., Aijun, S., Ling, Q., Tengda, X., Wei, X., Yan, D., et al. (2020) Ethnic Discordance in Serum Anti-Müllerian Hormone in Healthy Women: A Population Study from China and Europe. Reproductive BioMedicine Online, 40, 461-467. https://doi.org/10.1016/j.rbmo.2019.11.013
[35]
Andhavarapu, M., Maina, D., Murage, A. and Muteshi, C. (2022) Age-Related Changes in Serum Anti-Müllerian Hormone in Women of Reproductive Age in Kenya. South African Journal of Obstetrics and Gynaecology, 28, 57-61. https://doi.org/10.7196/SAJOG.2022.v28i2.2067
[36]
Bleil, M.E., Gregorich, S.E., Adler, N.E., Sternfeld, B., Rosen, M.P. and Cedars, M.I. (2014) Race/Ethnic Disparities in Reproductive Age: An Examination of Ovarian Reserve Estimates across Four Race/Ethnic Groups of Healthy, Regularly Cycling Women. Fertility and Sterility, 101, 199-207. https://doi.org/10.1016/j.fertnstert.2013.09.015
[37]
(2019) Infertility Workup for the Women’s Health Specialist: ACOG Committee Opinion, Number 781. Obstetrics & Gynecology, 133, e377-e384. https://doi.org/10.1097/AOG.0000000000003271
[38]
Seifer, D.B., Baker, V.L. and Leader, B. (2011) Age-Specific Serum Anti-Müllerian Hormone Values for 17,120 Women Presenting to Fertility Centers within the United States. Fertility and Sterility, 95, 747-750. https://doi.org/10.1016/j.fertnstert.2010.10.011
[39]
Doroftei, B., Mambet, C. and Zlei, M. (2015) It’s Never over until It’s over: How Can Age and Ovarian Reserve Be Mathematically Bound through the Measurement of Serum AMH-A Study of 5069 Romanian Women. PLOS ONE, 10, e0125216. https://doi.org/10.1371/journal.pone.0125216
[40]
Freeman, E.W., Sammel, M.D., Lin, H. and Gracia, C.R. (2012) Anti-Mullerian Hormone as a Predictor of Time to Menopause in Late Reproductive Age Women. The Journal of Clinical Endocrinology & Metabolism, 97, 1673-1680. https://doi.org/10.1210/jc.2011-3032
[41]
Bertone-Johnson, E.R., Manson, J.E., Purdue-Smithe, A.C., Steiner, A.Z., Eliassen, A.H., Hankinson, S.E., Rosner, B.A. and Whitcomb, B.W. (2018) Anti Mullerian Hormone Levels and Incidence of Early Natural Menopause in a Prospective Study. Human Reproduction, 33, 1175-1182. https://doi.org/10.1093/humrep/dey077
[42]
van Disseldorp, J., Faddy, M.J., Themmen, A.P., et al. (2008)Relationship of Serum Antimullerian Hormone Concentration to Age at Menopause. The Journal of Clinical Endocrinology & Metabolism, 93, 2129-2134. https://doi.org/10.1210/jc.2007-2093
[43]
Depmann, M., Eijkemans, M.J., Broer, S.L., et al. (2016)Does Anti-Mullerian Hormone Predict Menopause in the General Population? Results of a Prospective Ongoing Cohort Study. Human Reproduction, 31, 1579-1587. https://doi.org/10.1093/humrep/dew112
[44]
Cui, L., Qin, Y., Gao, X., et al. (2016)Anti-Müllerian Hormone: Correlation with Age and Androgenic and Metabolic Factors in Women from Birth to Postmenopause. Fertility and Sterility, 105, 481-485.E1. https://doi.org/10.1016/j.fertnstert.2015.10.017
[45]
Zhu, J., Li, T., Xing, W., Lin, H. and Ou, J. (2018) Chronological Age vs Biological Age: A Retrospective Analysis on Age-Specific Serum Anti-Müllerian Hormone Levels for 3280 Females in Reproductive Center Clinic. Gynecological Endocrinology, 34, 890-894. https://doi.org/10.1080/09513590.2018.1462317
[46]
Faddy, M.J., Gosden, R.G., Gougeon, A., et al. (1992)Accelerated Disappearance of Ovarian Follicles in Mid-Life: Implications for Forecasting Menopause. Human Reproduction, 7, 1342-1346. https://doi.org/10.1093/oxfordjournals.humrep.a137570
[47]
Faddy, M.J. and Gosden, R.G. (1996) A Model Conforming the Decline in Follicle Numbers to the Age of Menopause in Women. Human Reproduction, 11, 1484-1486. https://doi.org/10.1093/oxfordjournals.humrep.a019422
[48]
Thilagam, A. (2016) Mathematical Modelling of Decline in Follicle Pool during Female Reproductive Ageing. Mathematical Medicine and Biology: A Journal of the IMA, 33, 107-121. https://doi.org/10.1093/imammb/dqv006
[49]
Durlinger, A.L., Kramer, P., Karels, B., et al. (1999)Control of Primordial Follicle Recruitment by Anti-Mullerian Hormone in the Mouse Ovary. Endocrinology, 140, 5789-5796. https://doi.org/10.1210/endo.140.12.7204
[50]
Durlinger, A.L., Gruijters, M.J., Kramer, P., et al. (2001)Anti-Mullerian Hormone Attenuates the Effects of FSH on Follicle Development in the Mouse Ovary. Endocrinology, 142, 4891-4899. https://doi.org/10.1210/endo.142.11.8486
[51]
Carlsson, I.B., Scott, J.E., Visser, J.A., et al. (2006)Anti-Mullerian Hormone Inhibits Initiation of Growth of Human Primordial Ovarian Follicles in Vitro. Human Reproduction, 21, 2223-2227. https://doi.org/10.1093/humrep/del165
[52]
de Kat, A.C., van der Schouw, Y.T., Eijkemans, M.J.C., Herber-Gast, G.C., Visser, J.A., Verschuren, W.M.M. and Broekmans, F.J.M. (2016) Back to the Basics of Ovarian Aging: A Population-Based Study on Longitudinal Anti-Müllerian Hormone Decline. BMC Medicine, 14, Article No. 151. https://doi.org/10.1186/s12916-016-0699-y
[53]
Nelson, S.M., Messow, M.C., Wallace, A.M., et al. (2011)Nomogram for the Decline in Serum Anti-Mullerian Hormone: A Population Study of 9,601 Infertility Patients. Fertility and Sterility, 95, 736-741.E3. https://doi.org/10.1016/j.fertnstert.2010.08.022
[54]
Steiner, A.Z., Pritchard, D., Stanczyk, F.Z., Kesner, J.S., Meadows, J.W., Herring, A.H. and Baird, D.D. (2017) Association between Biomarkers of Ovarian Reserve and Infertility among Older Women of Reproductive Age. JAMA, 318, 1367-1376. https://doi.org/10.1001/jama.2017.14588
[55]
Practice Committee of the American Society for Reproductive Medicine (2020) Testing and Interpreting Measures of Ovarian Reserve: A Committee Opinion. Fertility and Sterility, 114, 1151-1157. https://doi.org/10.1016/j.fertnstert.2020.09.134
